Modified Podophyllotoxin Phenoxyacetamide Phenylacetate Derivatives: Tubulin/AKT1 Dual-Targeting and Potential...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths globally.
• Drug resistance remains a significant challenge in NSCLC treatment.
• The PI3K/AKT/mTOR pathway, particularly AKT, plays a crucial role in tumor development and drug resistance.

Purpose of the Study:

• To design and synthesize novel hybrid molecules targeting both tubulin and AKT for NSCLC treatment.
• To identify potent dual inhibitors with improved efficacy against drug-resistant NSCLC.
• To evaluate the anti-cancer activity and mechanism of action of lead compounds.

Main Methods:

• Computer-aided drug design was used to create hybrid molecules based on a podophyllotoxin (PPT) skeleton.
• A library of 20 novel compounds was synthesized and screened using the CCK8 assay.
• Affinity analysis and subsequent pharmacological experiments were conducted to assess compound activity and mechanism.

Main Results:

• Compound D1-1 exhibited potent inhibitory activity against H1975 cells (IC50 = 0.10 μM), significantly outperforming PPT and gefitinib.
• D1-1 demonstrated dual targeting of tubulin and AKT, retaining PPT's tubulin interaction while gaining AKT inhibitory capacity.
• Pharmacological studies confirmed D1-1's ability to inhibit proliferation and metastasis and induce apoptosis in H1975 cells by targeting both tubulin polymerization and AKT pathway activation.

Conclusions:

• The novel hybrid molecule D1-1 acts as a dual inhibitor of tubulin and AKT.
• D1-1 shows significant promise as a lead compound for developing new therapies for human NSCLC.
• This dual-targeting strategy offers a potential approach to overcome drug resistance in NSCLC.